Long‐term repopulation of aged bone marrow stem cells using young Sca‐1 cells promotes aged heart rejuvenation

Abstract

Reduced quantity and quality of stem cells in aged individuals hinders cardiac repair and regeneration after injury. We used young bone marrow (BM) stem cell antigen 1 (Sca‐1) cells to reconstitute aged BM and rejuvenate the aged heart, and examined the underlying molecular mechanisms. BM Sca‐1+ or Sca‐1− cells from young (2–3 months) or aged (18–19 months) GFP transgenic mice were transplanted into lethally irradiated aged mice to generate 4 groups of chimeras: young Sca‐1+, young Sca‐1−, old Sca‐1+, and old Sca‐1−. Four months later, expression of rejuvenation‐related genes (Bmi1, Cbx8, PNUTS, Sirt1, Sirt2, Sirt6) and proteins (CDK2, CDK4) was increased along with telomerase activity and telomerase‐related protein (DNA‐PKcs, TRF‐2) expression, whereas expression of senescence‐related genes (p16INK4a, P19ARF, p27Kip1) and proteins (p16INK4a, p27Kip1) was decreased in Sca‐1+ chimeric hearts, especially in the young group. Host cardiac endothelial cells (GFP−CD31+) but not cardiomyocytes were the primary cell type rejuvenated by young Sca‐1+ cells as shown by improved proliferation, migration, and tubular formation abilities. C‐X‐C chemokine CXCL12 was the factor most highly expressed in homed donor BM (GFP+) cells isolated from young Sca‐1+ chimeric hearts. Protein expression of Cxcr4, phospho‐Akt, and phospho‐FoxO3a in endothelial cells derived from the aged chimeric heart was increased, especially in the young Sca‐1+ group. Reconstitution of aged BM with young Sca‐1+ cells resulted in effective homing of functional stem cells in the aged heart. These young, regenerative stem cells promoted aged heart rejuvenation through activation of the Cxcl12/Cxcr4 pathway of cardiac endothelial cells.

Senescent mesenchymal stem/stromal cells and restoring their cellular functions

“…Implantation of genetically-modified old human MSCs with tissue inhibitor of matrix metalloproteinase-3 or VEGF promotes angiogenesis, prevents adverse remodeling, and preserves cardiac function to a similar extent compared with young hMSCs[ 122 ]. Stem cell antigen 1 (Sca-1)+ MSCs resident in the heart increase angiogenesis, and activate cell proliferation in the infarcted heart, which improves cardiac function after MI[ 123 , 124 ]. Overexpression of neuron-derived neurotrophic factor rejuvenates human ADSCs and BM-MSCs from the elderly, reduces the ischemic area, and repairs cardiac function after MI by improving angiogenesis and decreasing apoptosis[ 125 , 126 ].…”

Down-Regulation of Lnc-CYP7A1-1 Rejuvenates Aged Human Mesenchymal Stem Cells to Improve Their Efficacy for Heart Repair Through SYNE1

“…By bone marrow reconstitution animal model, we also demonstrated that young bone marrow Scal-1 cells can rejuvenate age animal heart function after MI. Examination of the underlying molecular mechanisms revealed that young bone marrow Scal-1 cells secreted more growth factors, such as Tgfβ1 and Cxcl12, in order to regenerate the aged heart ( Li et al, 2018 , 2019 ). In this study, we also detected paracrine functional changes, with down-regulation of lnc-CYP7A1-1 in O hBM-MSCs.…”

“…The potency of hBM-MSCs in the treatment of cardiovascular disease has been shown to decrease with the age of the donor ( Dong et al, 2018 ). This decreased potency of hBM-MSCs has a significant impact on the use of autologous stem cells for treating a predominantly older cohort of patients with cardiovascular disease ( Li S.-H. et al, 2013 ; Li et al, 2018 , 2019 ). Part of this reduced efficacy is due to hBM-MSCs taking on a senescent phenotype and losing their proliferative capacity ( Yan et al, 2017 ).…”

Considering Cause and Effect of Immune Cell Aging on Cardiac Repair after Myocardial Infarction

“…However, studies in mice show the benefits of bone marrow replacement in models of aging or chronic disease. Heterochronic (young to old) bone marrow transplant in 20-22 month old mice improves angiogenesis via upregulation of Cxcl12, Vegf and the inflammatory response post-MI [172,174,208]. Young bone marrow cell transplantation can also improve cognitive function and muscle repair in aged mice, implying a greater scope for bone marrow cell aging on systemic tissue aging [209][210][211].…”